RESUMO
Elevated levels of homocysteine (Hcy) in the blood, called hyperhomocysteinemia (HHcy), is a prevalent risk factor for it has been shown that Hcy induces oxidative stress and increases microglial activation and neuroinflammation, as well as causes cognitive impairment, which have been linked to the neurodegenerative process. This study aimed to evaluate the effect of mild hyperhomocysteinemia with or without ibuprofen and rivastigmine treatments on the behavior and neurochemical parameters in male rats. The chronic mild HHcy model was chemically induced in Wistar rats by subcutaneous administration of Hcy (4055 mg/kg body weight) twice daily for 30 days. Ibuprofen (40 mg/kg) and rivastigmine (0.5 mg/kg) were administered intraperitoneally once daily. Motor damage (open field, balance beam, rotarod, and vertical pole test), cognitive deficits (Y-maze), neurochemical parameters (oxidative status/antioxidant enzymatic defenses, presynaptic protein synapsin 1, inflammatory profile parameters, calcium binding adapter molecule 1 (Iba1), iNOS gene expression), and cholinergic anti-inflammatory pathway were investigated. Results showed that mild HHcy caused cognitive deficits in working memory, and impaired motor coordination reduced the amount of synapsin 1 protein, altered the neuroinflammatory picture, and caused changes in the activity of catalase and acetylcholinesterase enzymes. Both rivastigmine and ibuprofen treatments were able to mitigate this damage caused by mild HHcy. Together, these neurochemical changes may be associated with the mechanisms by which Hcy has been linked to a risk factor for AD. Treatments with rivastigmine and ibuprofen can effectively reduce the damage caused by increased Hcy levels.
Assuntos
Hiper-Homocisteinemia , Acetilcolinesterase/metabolismo , Animais , Homocisteína , Hiper-Homocisteinemia/induzido quimicamente , Hiper-Homocisteinemia/complicações , Hiper-Homocisteinemia/tratamento farmacológico , Ibuprofeno , Inflamação/complicações , Inflamação/tratamento farmacológico , Masculino , Estresse Oxidativo/fisiologia , Ratos , Ratos Wistar , Rivastigmina/farmacologia , Rivastigmina/uso terapêutico , Sinapsinas/metabolismoRESUMO
Beta-caryophyllene (BCP) is a phytocannabinoid whose neuroprotective activity has been mainly associated with selective activation of cannabinoid-type-2 (CB2) receptors, inhibition of microglial activation and decrease of inflammation. Here, we addressed the potential of BCP to induce neuritogenesis in PC12 cells, a model system for primary neuronal cells that express trkA receptors, respond to NGF and do not express CB2 receptors. We demonstrated that BCP increases the survival and activates the NGF-specific receptor trkA in NGF-deprived PC12 cells, without increasing the expression of NGF itself. The neuritogenic effect of BCP in PC12 cells was abolished by k252a, an inhibitor of the NGF-specific receptor trkA. Accordingly, BCP did not induce neuritogenesis in SH-SY5Y neuroblastoma cells, a neuronal model that does not express trkA receptors and do not respond to NGF. Additionally, we demonstrated that BCP increases the expression of axonal-plasticity-associated proteins (GAP-43, synapsin and synaptophysin) in PC12 cells. It is known that these proteins are up-regulated by NGF in neurons and neuron-like cells, such as PC12 cells. Altogether, these findings suggest that BCP activates trka receptors and induces neuritogenesis by a mechanism independent of NGF or cannabinoid receptors. This is the first study to show such effects of BCP and their beneficial role in neurodegenerative processes should be further investigated.
Assuntos
Canabinoides/farmacologia , Neuritos/metabolismo , Neurogênese/efeitos dos fármacos , Receptores de Canabinoides/metabolismo , Sesquiterpenos/farmacologia , Animais , Carbazóis/farmacologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Alcaloides Indólicos/farmacologia , Fator de Crescimento Neural/farmacologia , Proteínas do Tecido Nervoso/metabolismo , Neuritos/efeitos dos fármacos , Células PC12 , Sesquiterpenos Policíclicos , Ratos , Receptor trkA/antagonistas & inibidores , Receptor trkA/metabolismoRESUMO
Streptozotocin has been widely used to mimic some aspects of Alzheimer's disease (AD). However, especially in mice, several characteristics involved in the streptozotocin (STZ)-induced AD pathology are not well known. The main purpose of this study was to evaluate temporally the expression of AD-related proteins, such as amyloid-ß (Aß), choline acetyltransferase (ChAT), synapsin, axonal neurofilaments, and phosphorylated Tau in the hippocampus following intracerebroventricular (icv) administration of STZ in adult mice. We also analyzed the impact of STZ on short- and long-term memory by novel object recognition test. Male mice were injected with STZ or citrate buffer, and AD-related proteins were evaluated by immunoblotting assays in the hippocampus at 7, 14, or 21 days after injection. No differences between the groups were found at 7 days. The majority of AD markers evaluated were found altered at 14 days, i.e., the STZ group showed increased amyloid-ß protein and neurofilament expression, increased phosphorylation of Tau protein, and decreased synapsin expression levels compared to controls. Except for synapsin, all of these neurochemical changes were transient and did not last up to 21 days of STZ injection. Moreover, both short-term and long-term memory deficits were demonstrated after STZ treatment at 14 and 21 days after STZ treatment.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Colina O-Acetiltransferase/metabolismo , Hipocampo/metabolismo , Filamentos Intermediários/metabolismo , Transtornos da Memória/induzido quimicamente , Estreptozocina , Sinapsinas/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Animais , Modelos Animais de Doenças , Infusões Intraventriculares , Masculino , Camundongos , Fosforilação , Reconhecimento Psicológico/efeitos dos fármacos , Estreptozocina/administração & dosagemRESUMO
Cisplatin is the most effective and neurotoxic platinum chemotherapeutic agent. It induces a peripheral neuropathy characterized by distal axonal degeneration that might progress to degeneration of cell bodies and apoptosis. Most symptoms occur nearby distal axonal branches and axonal degeneration might induce peripheral neuropathy regardless neuronal apoptosis. The toxic mechanism of cisplatin has been mainly associated with DNA damage, but cisplatin might also affect neurite outgrowth. Nevertheless, the neurotoxic mechanism of cisplatin remains unclear. We investigated the early effects of cisplatin on axonal plasticity by using non-cytotoxic concentrations of cisplatin and PC12 cells as a model of neurite outgrowth and differentiation. PC12 cells express NGF-receptors (trkA) and respond to NGF by forming neurites, branches and synaptic vesicles. For comparison, we used a neuronal model (SH-SY5Y cells) that does not express trkA nor responds to NGF. Cisplatin did not change NGF expression in PC12 cells and decreased neurite outgrowth in both models, suggesting a NGF/trkA independent mechanism. It also reduced axonal growth (GAP-43) and synaptic (synapsin I and synaptophysin) proteins in PC12 cells, without inducing mitochondrial damage or apoptosis. Therefore, cisplatin might affect axonal plasticity before DNA damage, NGF/trkA down-regulation, mitochondrial damage or neuronal apoptosis. This is the first study to show that neuroplasticity-related proteins might be early targets of the neurotoxic action of cisplatin and their role on cisplatin-induced peripheral neuropathy should be investigated in vivo.
Assuntos
Cisplatino/farmacologia , Fator de Crescimento Neural/metabolismo , Crescimento Neuronal/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Animais , Axônios/efeitos dos fármacos , Axônios/metabolismo , Diferenciação Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Proteína GAP-43/metabolismo , Neuritos/efeitos dos fármacos , Neuritos/fisiologia , Células PC12 , Ratos , Receptores de Fator de Crescimento Neural/metabolismoRESUMO
Multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), are crucially dependent on the invasion of activated autoreactive lymphocytes and blood macrophages into the central nervous system (CNS). Proinflammatory mononuclear cells and activated local microglia mediate inflammation, demyelination and axonal damage at the target organ. Previously, we observed that the administration of a hybrid between the synapsin ABC domains and the B subunit of Escherichia coli heat labile-enterotoxin (LTBABC) to rats with EAE ameliorated disease by modulating the peripheral Th1 response to myelin basic protein (MBP). In the present study, we investigated the effect of LTBABC administration on proinflammatory cell frequency in the CNS of rats with EAE. Treatment with the hybrid in the inductive phase of EAE attenuated disease severity and diminished histological inflammatory infiltrates and demyelination in the spinal cord of rats with acute EAE. Lower frequencies of infiltrating and local macrophages as well as CD4+ T cells that produce the proinflammatory cytokines interferon-gamma (IFN-γ) and interleukin (IL)-17 were found at the target organ. Concomitantly, low levels of INF-γ and IL-17 and increased levels of IL-10 were measured in cultures of CNS infiltrating cells and spinal cord tissue. An increased frequency of CD4+CD25+Foxp3 cells was observed at the disease peak and at the beginning of the recovery stage. These results provide further evidence for the immunomodulatory properties of the fusion protein LTBABC in autoimmune demyelinating disease affecting the central nervous system.
Assuntos
Toxinas Bacterianas/administração & dosagem , Encefalomielite Autoimune Experimental/tratamento farmacológico , Enterotoxinas/administração & dosagem , Proteínas de Escherichia coli/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Medula Espinal/efeitos dos fármacos , Sinapsinas/administração & dosagem , Animais , Toxinas Bacterianas/genética , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/fisiologia , Bovinos , Células Cultivadas , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/fisiopatologia , Enterotoxinas/genética , Escherichia coli , Proteínas de Escherichia coli/genética , Feminino , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-17/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/fisiologia , Masculino , Ratos Wistar , Proteínas Recombinantes de Fusão/administração & dosagem , Medula Espinal/patologia , Medula Espinal/fisiopatologia , Sinapsinas/genéticaRESUMO
Synaptic transmission is an essential process for neuron physiology. Such process is enabled in part due to modulation of neurotransmitter release. Adenosine is a synaptic modulator of neurotransmitter release in the Central Nervous System, including neurons of medulla oblongata, where several nuclei are involved with neurovegetative reflexes. Adenosine modulates different neurotransmitter systems in medulla oblongata, specially glutamate and noradrenaline in the nucleus tractussolitarii, which are involved in hypotensive responses. However, the intracellular mechanisms involved in this modulation remain unknown. The adenosine A2a receptor modulates neurotransmitter release by activating two cAMP protein effectors, the protein kinase A and the exchange protein activated by cAMP. Therefore, an in vitro approach (cultured cells) was carried out to evaluate modulation of neurotransmission by adenosine A2a receptor and the signaling intracellular pathway involved. Results show that the adenosine A2a receptor agonist, CGS 21680, increases neurotransmitter release, in particular, glutamate and noradrenaline and such response is mediated by protein kinase A activation, which in turn increased synapsin I phosphorylation. This suggests a mechanism of A2aR modulation of neurotransmitter release in cultured cells from medulla oblongata of Wistar rats and suggest that protein kinase A mediates this modulation of neurotransmitter release via synapsin I phosphorylation.